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Cancer Immunology, Immunotherapy : CII Jul 2024Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of...
BACKGROUND
Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment.
MATERIALS AND METHODS
A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses.
RESULTS
A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders.
CONCLUSION
This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.
Topics: Humans; Nivolumab; Carcinoma, Renal Cell; Female; Male; Middle Aged; Aged; Adult; Kidney Neoplasms; Retrospective Studies; Aged, 80 and over; Young Adult; Adolescent; Antineoplastic Agents, Immunological; Follow-Up Studies
PubMed: 38954006
DOI: 10.1007/s00262-024-03741-2 -
Cancer Immunology, Immunotherapy : CII Jul 2024In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in...
In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in debulking and remodeling the tumor microenvironment. We investigated in vitro the killing efficacy and impact of treosulfan and fludarabine on ovarian cancer cells expressing mesothelin (MSLN) and effect on MSLN-targeting CAR T cells. Treosulfan and fludarabine had a synergetic effect on killing of SKOV3 and OVCAR4 cells. Sensitivity to the combination of treosulfan and fludarabine was increased when SKOV3 cells expressed MSLN and when OVCAR4 cells were tested in hypoxia, while MSLN cells surface expression by SKOV3 and OVCAR4 cells was not altered after treosulfan or fludarabine exposure. Exposure to treosulfan or fludarabine (10 µM) neither impacted MSLN-CAR T cells degranulation, cytokines production upon challenge with MSLN + OVCAR3 cells, nor induced mitochondrial defects. Combination of treosulfan and fludarabine decreased MSLN-CAR T cells anti-tumor killing in normoxia but not hypoxia. In conclusion, treosulfan and fludarabine killed MSLN + ovarian cancer cells without altering MSLN-CAR T cells functions (at low cytostatics concentration) even in hypoxic conditions, and our data support the use of treosulfan and fludarabine as conditioning drugs prior to MSLN-CAR T cell therapy.
Topics: Vidarabine; Humans; Female; Mesothelin; Ovarian Neoplasms; Receptors, Chimeric Antigen; GPI-Linked Proteins; Busulfan; Immunotherapy, Adoptive; Cell Line, Tumor; T-Lymphocytes; Tumor Microenvironment
PubMed: 38954005
DOI: 10.1007/s00262-024-03740-3 -
Cancer Immunology, Immunotherapy : CII Jul 2024To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed.
METHOD
The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines.
RESULTS
A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I = 38%, Z = 0.21 (P = 0.84)).
CONCLUSION
Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.
Topics: Humans; Pneumonia; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Neoplasms
PubMed: 38953977
DOI: 10.1007/s00262-024-03736-z -
Oncotarget Jul 2024
Topics: Pancreatic Neoplasms; Humans; Adenocarcinoma; Drug Screening Assays, Antitumor; Antineoplastic Agents
PubMed: 38953899
DOI: 10.18632/oncotarget.28556 -
The Journal of Experimental Medicine Sep 2024Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin...
Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.
Topics: Membrane Proteins; Humans; Endothelial Cells; Lung Diseases, Interstitial; Signal Transduction; Vascular Diseases; Golgi Apparatus; Interferons; Male; Gain of Function Mutation; Mutation; Infant
PubMed: 38953896
DOI: 10.1084/jem.20232167 -
Oncotarget Jul 2024Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib...
Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.
Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and . TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status . TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.
Topics: Humans; Trifluridine; Phenylurea Compounds; Animals; Pyridines; Drug Synergism; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Neovascularization, Pathologic; Xenograft Model Antitumor Assays; Neoplastic Stem Cells; Gastrointestinal Neoplasms; Uracil; Mice; STAT3 Transcription Factor; Thymine; Drug Combinations; Cell Line, Tumor; Pyrrolidines; Mutation; Antineoplastic Combined Chemotherapy Protocols; MAP Kinase Signaling System; Signal Transduction; Cell Proliferation; Angiogenesis
PubMed: 38953895
DOI: 10.18632/oncotarget.28602 -
Indian Journal of Public Health Apr 2024Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward...
Cancer patients suffer from complicated chemotoxicity. Pharmacogenomics can help stratify patients by predicting their response to treatment and susceptibility toward severe side effects. The spindle-assembly checkpoint (SAC) is an important pathway that is activated by platinum and taxane compounds and plays a crucial role in their cytotoxic activity. This study investigated a SAC component, Budding Uninhibited by Benzimidazoles 3 (BUB3), its expression, and genetic variants in advanced ovarian cancer patients treated with paclitaxel-carboplatin chemotherapy. Among 80 patients, BUB3 expression correlated with chemosensitivity, suggesting its potential as a predictive marker for chemotherapy response. However, high BUB3 expression was associated with a higher risk of poor survival. In addition, genetic polymorphisms in BUB3 (rs11248416 and rs11248419) were significantly linked to chemotherapy-related toxicities, with rs11248416 showing a negative impact on the patient's physical quality of life.
Topics: Humans; Female; Paclitaxel; Ovarian Neoplasms; Carboplatin; Middle Aged; M Phase Cell Cycle Checkpoints; Antineoplastic Combined Chemotherapy Protocols; Polymorphism, Single Nucleotide; Cell Cycle Proteins; Adult; Antineoplastic Agents; Quality of Life
PubMed: 38953826
DOI: 10.4103/ijph.ijph_809_23 -
Clinical Cardiology Jul 2024The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent.... (Observational Study)
Observational Study Comparative Study
INTRODUCTION
The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent. We compared the safety and effectiveness of the DESyne NES and the Orsiro bioresorbable polymer sirolimus-eluting stent (SES) in patients undergoing percutaneous coronary intervention (PCI).
METHODS
This was a retrospective, single-center, observational study. Between July 2017 and December 2022, patients who presented with chronic or acute coronary syndrome undergoing PCI with DESyne NES or Orsiro SES were consecutively enrolled in the present study. The primary endpoint, major adverse cardiovascular event (MACE), was a composite of cardiovascular death, target-vessel myocardial infarction, or clinically driven target-lesion revascularization.
RESULTS
A total of 776 patients (age 68.8 ± 12.2; 75.9% male) undergoing PCI were included. Overall, 231 patients with 313 lesions received NES and 545 patients with 846 lesions received SES. During a follow-up duration of 784 ± 522 days, the primary endpoint occurred in 10 patients (4.3%) in the NES group and in 36 patients (6.6%) in the SES group. After multivariate adjustment, the risk of MACE did not significantly differ between groups (NES vs. SES, hazard ratio 0.74, 95% CI, 0.35-1.55, p = 0.425). The event rate of individual components of the primary endpoint was comparable between the two groups.
CONCLUSIONS
Favorable and similar clinical outcomes were observed in patients undergoing PCI with either NES or SES in a medium-term follow-up duration. Future studies with adequately powered clinical endpoints are required for further evaluation.
Topics: Humans; Drug-Eluting Stents; Male; Female; Sirolimus; Retrospective Studies; Aged; Percutaneous Coronary Intervention; Treatment Outcome; Prosthesis Design; Coronary Artery Disease; Time Factors; Follow-Up Studies; Acute Coronary Syndrome; Risk Factors; Middle Aged; Coronary Angiography; Macrolides
PubMed: 38953595
DOI: 10.1002/clc.24317 -
General Physiology and Biophysics Jul 2024This study aims to determine the effect of sevoflurane (Sev) on nasopharyngeal carcinoma (NPC) in malignant behavior and mitochondrial membrane potential (MMP). NPC...
This study aims to determine the effect of sevoflurane (Sev) on nasopharyngeal carcinoma (NPC) in malignant behavior and mitochondrial membrane potential (MMP). NPC cells (5-8F and CNE2) were exposed to Sev at different concentrations and then tested for proliferation by CCK-8 and colony formation assays, apoptosis by flow cytometry, and invasion and migration by Transwell assays. In addition, the Warburg effect was examined by measurements of glucose consumption, lactic acid production, and adenosine triphosphate (ATP). Mitochondrial function was evaluated by reactive oxygen species (ROS) production, oxidative stress-related indexes, and mitochondrial membrane potential. Sev suppressed 5-8F and CNE2 cell proliferation, invasion, and migration, and enhanced apoptosis. Moreover, Sev dampened the Warburg effect by reducing glucose consumption, lactic acid production, and ATP, as well as decreasing hexokinase 2 and pyruvate kinases type M2 protein expressions. Also, Sev induced ROS production and malondialdehyde content and reduced superoxide and glutathione peroxidase levels. Finally, Sev caused damage to mitochondrial homeostasis through induction of cleaved caspase-3, cleaved caspase-9, and cytochrome c protein expression and reduction of MMP. Sev inhibits the malignant behavior of NPC cells by regulating MMP.
Topics: Sevoflurane; Humans; Membrane Potential, Mitochondrial; Nasopharyngeal Carcinoma; Cell Line, Tumor; Nasopharyngeal Neoplasms; Apoptosis; Cell Proliferation; Reactive Oxygen Species; Antineoplastic Agents; Dose-Response Relationship, Drug
PubMed: 38953572
DOI: 10.4149/gpb_2024014 -
Journal of Biochemical and Molecular... Jul 2024Cyclophosphamide (CP) is an antineoplastic drug widely used in chemotherapy. Curcumin (CUR) and piperine (PP) show a protective effect on neurodegenerative and...
Cyclophosphamide (CP) is an antineoplastic drug widely used in chemotherapy. Curcumin (CUR) and piperine (PP) show a protective effect on neurodegenerative and neurological diseases. This research was designed to measure several biochemical parameters in the brain tissue of CP-applied rats to investigate the impact of combined CUR-PP administration. The study evaluated six groups of eight rats: Group 1 was the control; Groups 2 and 3 were administered 200 or 300 mg/kg CUR-PP via oral gavage; Group 4 received only 200 mg/kg CP on day 1; Groups 5 and 6 received CP + CUR-PP for 7 days. Data from all parameters indicated that CP caused brain damage. Phosphorylated TAU (pTAU), amyloid-beta peptide 1-42 (Aβ1-42), glutamate (GLU), and gamma amino butyric acid (GABA) parameters were the same in Groups 4, 5, and 6. On the other hand, 8-hydroxy-2-deoxyguanosine (8-OHdG), nitric oxide (NO), interleukin-6 (IL-6), nuclear factor kappa beta (NF-kβ), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α) levels in the CP + CUR-PP groups were lower than those in the CP group (p < 0.05). However, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) parameters were higher in the CP + CUR-PP groups compared to the CP group (p < 0.05). It is thought that the similarity of Groups 5 and 6 with Group 4 in Aβ1-42, pTAU, GLU, and GABA parameters hinder the determination of treatment protection however, they might have a therapeutic effect if the applied dose or study duration were changed. This study attempted to evaluate the effects of a CUR-PP combination on CP-induced brain damage in rats by measuring biochemical parameters and performing histopathological examinations. Based on the findings, this CUR-PP combination could be considered an alternative medicine option in cases with conditions similar to those evaluated in this study.
Topics: Animals; Polyunsaturated Alkamides; Benzodioxoles; Curcumin; Piperidines; Alkaloids; Rats; Cyclophosphamide; Male; Brain Injuries; Rats, Wistar; Brain; Oxidative Stress; Neuroprotective Agents
PubMed: 38953502
DOI: 10.1002/jbt.23760